Project Summary. The long term goal of my research is to identify potential therapeutic targets and therapies to prevent and/or treat type 2 diabetes (T2D) and its associated cardiovascular complications as it is well known that T2D accelerates cardiovascular diseases and causes significant morbidity, mortality and economic burden. Insulin resistance plays a pivotal role in the pathogenesis of T2D and vascular endothelium actively regulates insulin action by facilitating tissue insulin delivery, a rate-limiting step that determines tissue interstitial concentrations of insulin. In muscle, insulin increases its own delivery by recruiting muscle microvasculature via the endothelial nitric oxide synthase pathway. This action alone could account for up to 40% of insulin-mediated whole body glucose disposal during insulin clamp. Evidence has confirmed that microvascular insulin resistance is present in the states of metabolic insulin resistance and all factors that cause metabolic insulin resistance have been shown to cause vascular insulin resistance as well. As it is in the microcirculation where nutrient and insulin uptake into muscle interstitium occurs, alleviation of microvascular insulin resistance would result in microvascular recruitment which expands the capillary exchange surface area and facilitates muscle insulin uptake and action. Angiotensin (Ang)-(1?7), a major component of the renin-angiotensin system, has been shown to exert both vasodilatory and insulin sensitizing actions. We have in our preliminary studies demonstrated that Ang-(1-7) potently recruits muscle microvasculature and increases insulin-mediated glucose disposal. The underlying mechanisms remain to be elucidated. The proposed study aims to examine whether Ang-(1-7)'s insulin sensitizing effect is via facilitating insulin delivery into muscle interstitium and/or via direct action on muscle myocytes as well as to identify the molecular pathways involved. The proposed study should help us better understand the pathophysiology of diabetes and may provide clinically relevant strategies to prevent or treat diabetes with microvascular endothelium as the therapeutic target. The proposed studies should help lay a solid foundation for my future career as an academic investigator in the field of diabetes and vascular biology. I will receive sufficient support from my department including necessary equipment, readily available resources, outstanding mentoring program and a rich academic environment to accomplish the proposed study. Support from this K Award will provide the key missing ingredient, the protected time, necessary for me to complete this project and my training to launch my independent research career.